Alcohol consumption and epigenetic age acceleration across human adulthood

The alcohol-associated biological aging remains to be studied across adulthood. We conducted linear regression analyses to investigate the associations between alcohol consumption and two DNA methylation-based biological age acceleration metrics in 3823 Framingham Heart Study participants (24–92 years and 53.8% women) adjusting for covariates. We also investigated whether the two epigenetic aging metrics mediated the association of alcohol consumption with hypertension. We found that higher long-term average alcohol consumption was significantly associated with biological age acceleration assessed by GrimAge acceleration (GAA) and PhenoAge acceleration (PAA) in middle-aged (45–64 years, n = 1866) and older (65–92 years, n = 1267) participants while not in young participants (24–44 years, n = 690). For example, one additional standard drink of alcohol (~14 grams of ethanol per day) was associated with a 0.71 ± 0.15-year (p = 2.1e-6) and 0.60 ± 0.18-year (p = 7.5e-4) increase in PAA in middle-aged and older participants, respectively, but the association was not significant in young participants (p = 0.23). One additional standard serving of liquor (~14 grams of ethanol) was associated with a greater increase in GAA (0.82-year, p = 4.8e-4) and PAA (1.45-year, p = 7.4e-5) than beer (GAA: 0.45-year, p = 5.2e-4; PAA: 0.48-year, p = 0.02) and wine (GAA: 0.51-year, p = 0.02; PAA: 0.91-year, p = 0.008) in middle-aged participant group. We observed that up to 28% of the association between alcohol consumption and hypertension was mediated by GAA or PAA in the pooled sample. Our findings suggest that alcohol consumption is associated with greater biological aging quantified by epigenetic aging metrics, which may mediate the association of alcohol consumption with quantitative traits, such as hypertension.

Median with quantiles was provided for continuous alcohol consumption variables. 1The cross-sectional alcohol consumption represented the latest cross-sectional total alcohol consumption.The binge drinking represented the recent binge drinking based the cross-sectional alcohol consumption and number of free-alcohol days per week.All statistics represented number of participants overlapped by the drinking category and the recent binge drinking.Four drinking categories were defined with long-term consumption.Non-drinkers were participants who had long-term average alcohol consumption equal to zero; light drinkers were defined as less than 1 drink per day for women and less than 2 drinks per day for men; at risk drinkers were defined as 1-2 drinks per day for women and 2-3 drinks per day for men; heavy drinkers were defined as more than 2 drinks per day for women and more than 3 drinks per day for men.The cross-sectional alcohol consumption represented the latest cross-sectional total alcohol consumption.The binge drinking represented the recent binge drinking based the cross-sectional alcohol consumption and number of free-alcohol days per week.

Supplementary Table 2. Association between long-term average alcohol consumption and EAAs.
All associations were adjusted for sex, physical activity index, education level, BMI, smoke pack-year, chronological age, age groups, and lab with the young-age group (22-44 years) as the reference.The beta () coefficients represented the increase in EAA with one additional drink of long-term total alcohol consumption in middle-aged (45-64 years) or older (≥ 65 years) participants, compared to the young-age participants.Overall p, p value of the interaction term (alcohol*age group).Abbreviations: LCI: low confidence interval; UCI: upper confidence interval; IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.AGING All associations were adjusted for sex, physical activity score, education level, BMI, smoke pack-year, chronological age, and lab.The  coefficients represented the increase in EAA with one additional drink of long-term average alcohol consumption in each group.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.

Table 6 . Overlap between drinking category and binge drinking.
All associations were adjusted for sex, physical activity index, education level, BMI, smoke pack-year, chronological age, and lab.The  coefficients represented the increase in EAA with one additional drink of cross-sectional alcohol consumption in each group.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.

Table 7 . Association between recent binge drinking and EAAs.
All associations were adjusted for sex, physical activity index, education level, BMI, smoke pack-year, chronological age, and lab.The  coefficients represented the increase of EAA in participants with recent binge drinking, compared to those without recent binge drinking in each group.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.AGING

Table 8 . Association between long-term average alcohol consumption and EAAs with white blood cell compositions in young group. Without white blood cell compositions Adjust for white blood cell compositions
All associations were adjusted for sex, physical activity score, education level, BMI, smoke pack-year, chronological age, and lab.Models with white blood cells additionally adjusted for CD8+ T, CD4+ T, natural killer cells, B cells, monocytes, and granulocytes.All models contained same set of samples (n = 690).The  coefficients represented the increase in EAA with one additional drink of long-term average alcohol consumption in the young group.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.

Supplementary Table 9. Association between long-term average alcohol consumption and EAAs with white blood cell compositions in middle-aged group. Without white blood cell compositions Adjust for white blood cell compositions
All associations were adjusted for sex, physical activity score, education level, BMI, smoke pack-year, chronological age, and lab.Models with white blood cells additionally adjusted for CD8+ T, CD4+ T, natural killer cells, B cells, monocytes, and granulocytes.All models contained same set of samples (n = 1852).The  coefficients represented the increase in EAA with one additional drink of long-term average alcohol consumption in the middle-aged group.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.

Table 10. Association between long-term average alcohol consumption and EAAs with white blood cell compositions in older group. Without white blood cell compositions Adjust for white blood cell compositions
lab.Models with white blood cells additionally adjusted for CD8+ T, CD4+ T, natural killer cells, B cells, monocytes, and granulocytes.All models contained same set of samples (n = 1255).The  coefficients represented the increase in EAA with one additional drink of long-term average alcohol consumption in the older group.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA: GrimAge acceleration; PAA: PhenoAge acceleration.AGING

Supplementary Table 12. Association between long-term average alcohol consumption and EAAs with long-term covariates.
All associations were adjusted for sex, physical activity index, education level, BMI, smoking status, chronological age, and lab with non-drinker as the reference.The  coefficients represented the increase in EAA with one additional drink of long-term total alcohol consumption in former drinkers or current drinkers, compared to increase in non-drinkers in each age group or the pooled sample.Abbreviations: IEAA: intrinsic epigenetic age acceleration; EEAA: extrinsic epigenetic age acceleration; EAASkinBlood: epigenetic age acceleration with skin and blood clock; GAA, GrimAge acceleration; PAA, PhenoAge acceleration.

Table 15. Effects of alcohol consumption and EAAs on hypertension.
All associations were adjusted for sex, physical activity index, education level, BMI, smoke pack-year, chronological age, and lab.Abbreviations: LCI: low confidence interval; UCI: upper confidence interval.Abbreviations: GAA: GrimAge acceleration; PAA: PhenoAge acceleration.

Table 16. Mediation analysis of EAAs on the association of long-term alcohol consumption and hypertension.
All associations were adjusted for sex, physical activity index, education level, BMI, smoke pack-year, chronological age, and lab.Abbreviations: GAA: GrimAge acceleration; PAA: PhenoAge acceleration.